Antimicrobial cationic polyamines

Patent metadata

Field	Value
Publication number	US-9399044-B2
Application number	US-201414288782-A
Country	US
Kind code	B2
Filing date	May 28, 2014
Priority date	May 28, 2014
Publication date	Jul 26, 2016
Grant date	Jul 26, 2016

Abstract

Antimicrobial, non-hemolytic cationic polyamines were prepared by treating partially N-acylated polyethylenimines and/or partially oxidized polyethylenimines with a protic acid. The cationic polyamines can have a linear or branched polyethylenimine backbone structure. Preferably, the cationic polyamines comprise pendant urea groups, which can be introduced via a cyclic carbonate comprising a pendant urea group. The cationic polyamines can be active against a tuberculosis mycobacterium at low concentration. The cationic polyamines are also effective against Gram-negative Escherichia coli and Pseudomonas aeruginosa , Gram-positive Staphylococcus aureus , and fungus Candida albicans in solution and in the form of a film.

First claim

What is claimed is:

1. A method, comprising:
treating a medical condition caused by at least one bacterium by contacting the bacterium with a cationic polyamine, thereby killing the bacterium, wherein the cationic polyamine has a polymer backbone comprising:
i) a positive-charged first ethylenimine unit of formula (2):

wherein X ⊖ is a negative-charged counterion bound by non-covalent association with the positive charged nitrogen labeled 1, and
ii) a non-charged second ethylenimine unit of formula (3):

wherein K′ comprises at least one carbon;
and wherein
no backbone nitrogen of the cationic polyamine is present as a quaternary ammonium salt,
the cationic polyamine has a hemolysis HC20 value of greater than 1000 mg/L, and
the first ethylenimine unit and the second ethylenimine unit of the polymer backbone are directly and/or indirectly covalently linked.

2. The method of claim 1 , wherein the first ethylenimine unit and the second ethylenimine unit are linked in a head to tail arrangement, wherein a nitrogen labeled 1 is the head and a carbon labeled 3 is the tail.

3. The method of claim 1 , wherein the bacterium is a mycobacterium.

4. The method of claim 1 , wherein K′ is a C 1 -C 10 alkyl group.

5. The method of claim 1 , wherein K′ comprises a urea group.

6. The method of claim 1 , wherein K′ comprises a group that completes a urea group with the backbone nitrogen labeled 1.

7. The method of claim 1 , wherein the cationic polyamine is a linear cationic polyamine having one polymer chain branch and two peripheral polymer chain ends.

8. The method of claim 1 , wherein the cationic polyamine is a branched cationic polyamine having two or more intersecting polymer chain branches and three or more peripheral polymer chain ends.

9. The method of claim 1 , wherein K′ is ethyl.

10. The method of claim 1 , wherein the cationic polyamine comprises the first ethylenimine unit and the second ethylenimine unit in a molar ratio of about 1:1 to about 400:1, respectively.

11. The method of claim 1 , wherein the polymer backbone of the cationic polyamine comprises an oxidized ethylenimine unit (third ethylenimine unit) of formula (7):

12. The method of claim 1 , wherein *—C(═O)—K′ of formula (3) has a structure selected from the group consisting of:

13. The method of claim 1 , wherein the non-charged second ethylenimine unit of formula (3) has a structure according to formula (6):

wherein each R 2 is a monovalent radical independently selected from the group consisting of hydrogen, alkyl groups comprising 1 to 30 carbons, and aryl groups comprising 6 to 30 carbons, and wherein at least one R 2 comprises at least one carbon.

14. A drug, comprising:
a cationic polyamine, wherein the cationic polyamine has a polymer backbone comprising:
i) a positive-charged first ethylenimine unit of formula (2):

wherein X ⊕ is a negative-charged counterion bound by non-covalent association with the positive charged nitrogen labeled 1, and
ii) a non-charged second ethylenimine unit of formula (3):

wherein K′ comprises at least one carbon;
and wherein
no backbone nitrogen of the cationic polyamine is present as a quaternary ammonium salt,
the first ethylenimine unit and the second ethylenimine unit are directly and/or indirectly covalently linked,
the drug is effective in killing a bacterium, and
the drug has a hemolysis HC20 value of greater than 1000 mg/L.

15. The drug of claim 14 , wherein the drug is effective in killing a mycobacterium.

16. The drug of claim 14 , wherein the drug has the form of an injectable solution, the solution comprising the cationic polyamine and water.

17. The drug of claim 14 , wherein the drug has the form of a pill.

18. The drug of claim 14 , wherein the drug has the form of an ointment.

19. A method, comprising:
forming a mixture comprising i) a base polyamine selected from the group consisting of polyethylenimines, partially N-acylated polyethylenimines, and combinations thereof, and ii) a solvent,
treating the mixture with oxygen and/or a peroxide, thereby forming an oxidized base polyamine; and
treating the oxidized base polyamine with a protic acid, thereby forming an oxidized cationic polyamine having a polymer backbone that comprises:
a positive-charged first ethylenimine unit of formula (2):

wherein X ⊕ is a negative-charged counterion bound by non-covalent association with the positive charged nitrogen labeled 1, and
an oxidized ethylenimine unit of formula (7):

wherein
no backbone nitrogen of the cationic polyamine is present as a quaternary ammonium salt,
the first ethylenimine unit and the oxidized ethylenimine unit are directly and/or indirectly covalently linked,
the cationic polyamine is effective in killing a bacterium, and
the cationic polyamine has a hemolysis HC20 value of greater than 1000 mg/L.

20. An antimicrobial film, wherein the film comprises a cationic polyamine having a polymer backbone that comprises:
i) a positive-charged first ethylenimine unit of formula (2):

wherein X ⊕ is a negative-charged counterion bound by non-covalent association with the positive charged nitrogen labeled 1, and
ii) a non-charged second ethylenimine unit of formula (3):

wherein K′ comprises at least one carbon;
and wherein
no backbone nitrogen of the cationic polyamine is present as a quaternary ammonium salt,
the first ethylenimine unit and the second ethylenimine unit are directly and/or indirectly covalently linked.

21. The antimicrobial film of claim 20 , wherein the film is effective in killing a fungus.

22. The antimicrobial film of claim 20 , wherein the film is effective in inhibiting growth of a biofilm.

23. The antimicrobial film of claim 20 , wherein the cationic polyamine of the film comprises an ethylenimine unit of formula (D-1):

wherein C′ comprises a catechol group.

24. The antimicrobial film of claim 23 , wherein C′ is a moiety selected from the group consisting of

Assignees

• IBM
• Agency Science Tech & Res

Inventors

• Cheng Wei
• Ding Xin
• Garcia Jeannette M
• Hedrick James L
• Yang Chuan
• Yang Yi Yan

Classifications

• A01N47/30

  Derivatives containing the group >N—CO—N aryl or >N—CS—N—aryl · CPC title

• C08G73/0226

  Quaternisation of polyalkylene(poly)amines · CPC title

• A01N25/10

  Macromolecular compounds · CPC title

• A01N33/04

  Nitrogen directly attached to aliphatic or cycloaliphatic carbon atoms · CPC title

• A01N37/46

  N-acyl derivatives · CPC title